Amino esters



Patented June 15, 1954 Taunus) Main); Hoe'chst Lucius & Germany,

and Walter Aumiiller, Frankfurt. Germany, assignorsv to, .Farliwerke-Aktiengesellschaft' vormals Meister Bruning, Frankfurt (Main), Hochst, aGerman company- No Drawing. Application June 30,, 1953,, "Serial .No.365,268

Cla'iins priority, "application Germany May 26, 1951 6,.Cl'aims. (Cl.260294.3)

l Thepresent invention relates to. basic. ethers and to a process ofpreparing them, The new basic ethers obtained according to the presentinvention are compounds having the general formula in which X represents00 or CH2, R1: a lower alkyl, and R2 and' Rs stand for hydrogen, loweralkyl or together with N for a piperidino or pyrro'lidino radical. Thesecompounds: and their salts have valuable therapeutic properties andespecially the benzophenonederivatives, i. e. the compounds in which X"stands for C0, are distinguished by their pharmacological effect.

First of all, the compounds are excellent antispasmodics, but they havealso a strong local anesthetic effect. Thelocal anesthetic effect 60f 4'p-piperidino-ethoxy -2 carbethoxybenzophenone hydrochloride at theguinea pigs wheal, for instance, is twice as strong as that ofparaamino-benzoyldiethylamino-ethanol hydrochlorideand, compared to theknown compound, the surface anesthetic eifect is likewise twice asstrong. The compound of the present invention possesses a verygoodatropineeffect and; 'in addition, an anal'eptic effect. the kind ofamine, it has the same" effect as atropine on. the lentine spasmintheintestine; it sh0ws.only.about' of the .secretioninhibiting' effectof the glands compared to atropine. The low salivation-inhibiting,eifect. together with a. good antispasmodic efiect. on the smoothmusculature of the. intestine. favors. the therapeutic application of.4'- p piperidinmethoxy 2carbethoxy-benzophenone hydrochloride forspasmodic. obstipation, intestinal spasms, ileus,

pylorospasm of infants as Well as .ffor' renal and biliary colic.

4'- p pyrrolidino-ethoxy-Z-carbethoxy-benzophenone hydrochloride and 4-B-piperidino-ethoxy-2-carbethoxy-diphenyl-methanehydrochloride show asimilar effect; 4'-}3'-piperidino-eth'- oxy-Z-carbethoxy=diphenylmethanehydrochl'ois ride, too, is distinguished bya. very goodparasympatholytic effect. As compared with 4"'-/3'- piperidino-ethoxy -2carbethoxy-benzophenone hydrochloride, the 4- s-piperidiho-ethbxy-Zcarbmethoxy-benzoephenone hydrochloridepossesses a smaller enact onthe'lenth'ine spasm, but has-a far superior effect on the histaminespasm.

Whilst, according to Compounds. of thegeneralv formula s. COOR in whichX, R1, R2, and R3 have the above meaning, canbeobtained in variousmanners. Compounds of the general formula in which, X. stands for CO orCH2, for instance, can. in. any desired sequence, be esterified at thecarboxyl group, and etherified at the phenolic hydroxyl group-with analiphatic compound carrying a basic. nitrogenous radical of aliphaticnature.

4'-Oxybenzophenone-2-carboxy1ic acid can, for example,be esterified withan aliphatic alcohol of low molecular weight such as methanol, ethaqnol, .propanol, isopropyl alcohol, butanol or isobutyl alcohol. Theresulting 4.'-oxybenzophe.- none--2-carboxylic acid esters, can thentbeetherified with aliphatic compounds carrying a basic nitrogenous radicalof aliphatic nature.

As-aliphatic radicals substituted by a basicnitrogenous radical ofaliphatic nature there may be mentioned: amino alkyl such as aminoethyl, dialkyl amino alkyl such as dimethyl amino ethyl, diethyl amino.ethyl, imidazolino methyl, pyrrolidino ethyl, piperidinoalkyl, amidinoalkyl, and the like. The piperidinoalkyl radical, and above all thepiperidino ethyl radical, are particularlyv suitable radicals of thekindin question. 4'-5-piperidino-ethoxy-2-carbethoxy' benzophenonehydrochloride, for instance, is distinguished by its excellentpharmacological effect.

Starting from esterified diphenyl methane carboxylic acids, thecorresponding diphenyl methane derivatives can be obtained in the samemanner.. .It isalso possible to prepare the basic ethers of4'-oxybenzophenone-2-carboxylic acid or4.-oxy-dipheny1-methane-2-carboxylic acid by esterifying the carboxylicacids already etherified in 4'-position. 4'-oxybenzophenone carboxylic.acid-(2) may also be used as starting material' for. the preparation ofbasic ethers; of 4'- oxydiphenyl-methane carboxylic acid esters. In thiscase,,the keto bridge is converted, by an intermediate process step, forinstance by way .of the benzhydrol, into a methylene group, forexamp1e,jby reduction with zinc dust andammonia.

Various. methods may be applied for the ethfication, such as cyanalkylether of the formula COORi in which X1 and R1 have the above meaning.These intermediates can be converted, in a manner known as such, intoamidines or imidazolines or can be reduced to primary amino ethers.

The following examples serve to illustrate the invention, but they arenot intended to, limit it thereto:

Example 1 29 grams of 4-oxybenzophenone-2-carboxylic acid methyl esterin 280 cc. of dry methyl ethyl ketone are boiled for 3% hours underreflux with 33.4 grams of B-piperidino-ethyl chloride and 31 grams ofdry potassium carbonate. After cooling, the mixture is filtered, methylethyl ketone and the excess of the base are removed by distillationunder reduced pressure, and the residue is shaken with ether and causticsoda solution. The resulting ether solution is washed with water anddried with potassium carbonate. On addition of alcoholic hydrochloricacid to the ether solution until an acid reaction to Congo paper isobtained, the hydrochloride of4'-B-piperidino-ethoxy-2-carbomethoxy-benzophenone precipitates in asmear-y state. On triturating with isopropyl alcohol it becomescrystalline. It can be recrystallized from isopropyl alcohol. The yieldamounts to 22 grams. The product melts at 168 C.-169 C.

Example 2 40.5 grams of 4-oxybenzophenone-2-carboxylic acid ethyl esterare dissolved in 390 cc. of dry acetone and boiled under refiux for 3%hours with 33.1 grams of fi-piperidinoethyl chloride and 41.4 grams ofdry potassium carbonate. After cooling, the mixture is filtered withsuction. The filtrate is rendered acid to Congo paper by addingalcoholic hydrochloric acid.4-,B-piperidino-ethoxy-benzophenone-2-carboxy1ic acid ethyl esterhydrochloride crystallizes out; It is filtered off with suction andrecrystallized from ethanol. The yield amounts to 56.2 grams. Theproduct melts at 179 C.180 C.

Example 3 2'? grams of 4'-oxybenzophenone-2-carboxylic acid butyl esterin 270 cc. of dry acetone are boiled under reflux for 3% hours withgrams of fl-piperidinoethyl chloride and 28 grams of dry potassiumcarbonate. After filtration With suction, the filtrate is rendered acidto Congo paper by addition of alcoholic hydrochloric acid, and thehydrochloride of 4B-piperidinoethoxy-(2)- carbobutoxy-benzophenone isprecipitated with ether. As the salt precipitates at first in a smearystate it is, for further purification, converted into the oxalate, whichis easily recrystallized from ethanol. The product melts at 133 C.-134C.

For conversion into the citrate, the base is set free from the oxalateby means of sodium carbonate solution, taken up in ether andprecipitated, by addition of an alcoholic solution of citric acid, asthe primary citrate which is recrystallized from alcohol.

Example 4 9 grams of 4-oxybenzophenone-Z-carboxylic acid ethyl ester incc. of dry acetone are boiled for 2 /2 hours under reflux with 9 gramsof [3-diethylaminoethyl chloride and 9.2 grams of dry potassiumcarbonate. After standing overnight, the mixture is filtered withsuction. The filtrate is rendered acid to Congo paper by addingalcoholic hydrochloric acid. On addition of ether, smears precipitatewhich solidify after some time. The ether is decanted, and the crystalsare recrystallized from ethanol. 4'-;8-diethylaminoethoxy 2 carbethoxybenzop-henone hydrochloride melting at 144 C. is obtained in a goodyield.

Example 5 15 grams of 4-oxy-diphenylmethane,-2-carboxylic acid methylester in 150 cc. of dry methyl ethyl ketone are boiled under reflux with13.7 grams of fi-piperidino-ethyl chloride and -18 grams of drypotassium carbonate for 3% hours. After cooling and filtering, thefiltrate is acidified with alcoholic hydrochloric acid. 25 grams of thecrude 4'-fi-piperidino-ethoxy-2-carbomethoxy, diphenyl-methanehydrochloride melting at 148 C.l49 C. crystallize out. After repeatedrecrystallization from ethanol the substance melts at 154 C.-l55 C.

Example 6 9.5 grams of l-oxy-diphenyl-methane-Z-carboxylic acid ethylester and 8.3 grams of fi-piperidino-ethyl chloride are boiled underreflux in the presence of 10 grams of dry potassium carbonate in cc. ofmethyl ethyl ketone for 3% hours. After filtration with suction, methylethyl ketone and the excess of the chlorine base are removed bydistillation under reduced pressure, and the residue is taken up inether. The ether solution is shaken with a dilute caustic soda solutionand water and is dried over potassium carbonate. By acidification withan acetonic solution of oxalic acid, a precipitate of the acid 4' Bpiperidino ethoxy 2 carbethoxy diphenylmethane oxalate, melting at 136C. after recrystallization from water, is obtained. In order to convertthe product into the citrate, the base is set free by a solution ofsodium carbonate, taken up in ether and precipitated as the primarycitrate by addition of an alcoholic solution of citric acid. Afterrecrystallization from methanol, the primary4-B-piperidino-ethoxy-2-carbethoxy-diphenylmethane citrate decomposes at112 C.-113 C.

Example 7 42 grams of 4'-oxy-benzophenone-2-carboxylic acid ethyl esterin 420 cc. of dry acetone are boiled under reflux with 35 grams ofB-pyrrolidino ethyl chloride and 43 grams of finely powdered, drypotassium carbonate for 4 hours on a steam bath The hot solution isfiltered oil. allowed to cool, and alcoholic hydrochloric acid is addeduntil the solution shows an acid reaction towards Congo paper.4-p-pyrrolidinoethoxy-2-carbethoxy-benzophenone hydrochlorideprecipitates in a good yield. For further purification, the crudeproduct is dissolved in irazccaec ro ...E:z: mplei 8 40.5 grams of4-oxy-benzophenone-2-carboxylic acid ethyl ester in 360 cc. of methylethyl ketone are boiled under reflux with 12.3

grams of chloro-acetonitrile in the presence of 41.4 grams of drypotassium carbonate and 0.3 gram of potassium iodide for 3 hours. Afterfiltration, the solution is evaporated to dryness under reducedpressure. The residue is dissolved by shaking with dilute sodiumcarbonate solution and ether and the solution obtained is extractedrepeatedly with dilute sodium or potassium hydroxyde solution. The ethersolution is washed with water and dried with potassium carbonate. Theresidue obtained after evaporation of the solvent becomes slowlycrystalline. It is recrystallized from ethanol.4'-cyanomethoxy-2-carbethoxy-benzophenone, melting at 80 C.-81 C., isobtained in a yield of 32.4 grams.

grams of 4'-cyanomethoxy-2-carbethoxybenzophenone are dissolved in 400cc. of methanol, and, after addition of 3.3 grams of ammonia, shaken atroom temperature with hydrogen in the presence of Barley-nickel. Afterabsorption of the calculated quantity of hydrogen, the catalyst isfiltered oif and the solution is evaporated to dryness under reducedpressure. The residue is shaken with dilute sodium carbonate solutionand ether, and the ether solution is dried with potassium carbonate. Byaddition of an ether solution of oxalic acid, 4' aminoethoxy 2carbethoxy benzophenone oxalate precipitates which, afterrecrystallization from methanol, melts at 132 C.

Example 9 42.6 grams of 4'-oxy-benzophenone-2-carboxylic acid ethylester in 300 cc. of methyl ethyl ketone are boiled under reflux for 4hours with 28.2 grams of w-chloromethyl-imidazoline hydrochloride in thepresence of 24 grams of dry potassium carbonate and 3 grams of potassiumiodide. After filtration with suction, methyl ethyl ketone is removed bydistillation under reduced pressure, and the resulting viscous residueis dissolved by shaking with dilute caustic soda solution and aceticacid ethyl ester. The acetic acid ethyl ester solution is againextracted twice with dilute caustic soda solution, washed with water anddried with potassium carbonate. After filtration, the solution isacidified with an acetonic solution of oxalic acid, and ether is addeduntil the formation of the precipitate ceases. By treating with warmethanol the halfcrystalline precipitate so obtained is freed fromadhering smears, and is then filtered off with suction. The resulting4-imidazolino-methoxy- 2-carbethoxy-benzophenone oxalate isrecrystallized from ethanol. It melts at 193 C. with decomposition.

Example 10 12.1 grams of 4'-oxybenzophenone-2-carboxylic acid are addedto a sodium methylate solution which was prepared from 2.3 grams ofsodrochloric 6 diumc-andabout F cc. -of' methanol. 2A. clear solution isobtained which is evaporatedisto dryness .under reduced pressure. Theresulting crystal cakeis .digested *with benzene, again evaporatedl-todryness and, after pulv-erization, added toa solution of 30 grams of, epiperidinoethyl chloride in 200. .cc. of .methyl. ethylzketone.

.After. boilingundenrefiux .for 7. .hours, the precipitatedsddiumchloride-is. filtered off, and the solventiis removed by distillationunder reduced pressure. .The residue is dissolved in dilute'hyacid,'and' the" non-basicconstituents are'r'removed by extraction with ether."When adding a strong solution of causticsdda, an oil separates which"does not=-dissolve even when heated. It is separated and taken up inethanol. After evaporation of the alcohol, preferably with addition of alittle benzene, a crystal cake is obtained which is recrystallized fromisopropyl alcohol. The crystals so purified are dissolved in a littlewater, and the alkaline solution is neutralized. Very soon the innersalt of 4'-,8- piperidinoethoxy 2 carboxy benzophenone crystallizes outin beautiful, colorless crystals. The salt is slightly soluble in theusual organic solvents, but it dissolves in dilute hydrochloric acid andin ammonia. It melts at 238 C.-239 C.

5 grams of 4-B-piperidinoethoxy-carboxy- (2) -benzophenone (inner salt)are dissolved in 100 cc. of ethanol after addition of 5 grams ofconcentrated sulfuric acid. The solution is boiled under reflux for 4hours, and is concentrated under reduced pressure. The residue is shakenwith ether and an excess of potassium carbonate solution. The ethersolution is dried with potassium carbonate. After filtration, alcoholichydrochloric acid is added to the solution. A smeary precipitate of4'-s-piperidinoethoxy-2-carbethoxy-benzophenone hydrochloride isobtained which turns crystalline after a short time. The product isfiltered off with suction and recrystallized from ethanol. It melts at179 C.-180 C.

This application is a continuation-in-part of application Serial No.289,006, filed May 20, 1952.

We claim:

1. A compound selected from the group which consists of a basic ether ofthe general formula and salts of said basic ether.

3. A compound selected from the group which consists of a basic ether ofthe formula om om Q-om-Q-oomonm om a CHr-C COOCaHs and salts of saidbasic ether.

7 4'. A compound selected from thegroup which 6. A compound selectedfrom the group which consists of a basic ether of the formula consistsof a basic ether of the formula 0 CH2--CH2 HQ CHz-CHI -o 0.0H:.OH:.N CH:

\OH g 5 -oo-o.om.om.n L oooom r CHa' m and salts of said basic ether.000cm 5. A compound selected from the group which and Salts of Saidbasic ethen consists of a basic ether of the formula CH CH 10 7 000011;and salts of said basic ether. 5

No references cited.

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF A BASIC ETHER OF THE GENERAL FORMULA 